This is a 3-center (PIs: Drs. Otto, Pollack, Tolin) collaborative R01. In this application, we propose to further validate and expand upon one of the apparent striking successes of translational research. Specifically, basic research on the neural circuitry underlying fear extinction led to the examination of d-cycloserine, a partial agonist at the NMDA receptor in the amygdala, as an agent capable of enhancing extinction learning (Davis et al., 2006a;Davis et al., 2006b). Following successful validation of this strategy in the animal laboratory, Ressler et al. (2004) showed that single doses of d-cycloserine (DCS) could enhance extinction in a human exposure paradigm for height phobic adults. This exciting initial finding was replicated by our research team for the treatment of social anxiety disorder in outpatients (Hofmann et al., 2006), and we also have completed a pilot study indicating similar benefits for the treatment of other anxiety disorders. As discussed by Anderson and Insel (2006), these findings have the potential to foster significant advances in the treatment of anxiety disorders. The present study represents the further application of DCS for augmenting the effects of exposure- based cognitive-behavior therapy (CBT), now applied to the treatment of panic disorder with or without agoraphobia. In this application we propose a double-blind randomized controlled trial, conducted at three treatment sites, to compare the relative benefit of augmenting exposure-based CBT with DCS as compared to placebo for patients with panic disorder. In addition, by studying variability at specific gene sites as a predictor of treatment response, particularly for the effects of DCS augmentation, we seek to identify which patients may be particularly responsive to this form of brief, combined treatment. This study capitalizes on the recent successes in translational research to investigate the benefits of the addition of d-cycloserine to a program of brief exposure-based CBT for the treatment of panic disorder with or without agoraphobia. This study addresses an important public health issue by assessing an intervention that may help lead to a more efficient and effective application of empirically-based psychosocial interventions for the treatment of panic disorder and other anxiety disorders. This novel strategy of combining exposure-based treatment and d-cycloserine remains a particularly promising strategy among disappointing alternatives for the treatment of individuals with anxiety disorders, and our research will also provide valuable information on potential genetic moderators of both CBT efficacy as well as d-cycloserine enhancement of this efficacy.